Process of making alkamins.



UNITED STATES ERNEST FOURNEAU, OF PARIS, FRANCE.

PROCESS OF M KING ALKAMINS.

Specification of Letters Patent.

Patented Aug. 14, 1906.

Original application filed Marcl1 21, 1904, Serial No. 199,283. Divided and this application filed June 3,1906. Serial No. 268.636.

amino group. A art from some natural alkaloids which be ong to the class of the alkamins (amino alcohols) comparatively few representatives of this class of bodies are known in the aromatic series and in the higher links of the fatty series.

In the course of his work on the constitution of morphine Knorr was led to study aminoethyl alcohol (ethanolamin) and aminopropylalcohol, (propanolamin;) but as he ursued his researches in a definite direction he did not try to obtain a series of bodies which could not interest him. Besides, he lacked a general method which would have enabled him easily to produce exactly-defined chlorhydrins, and in consequence the corresponding alkamins. Furthermore, no one had hitherto foreseen the great importance of certain alkamins from a technical standpoint. Now it was found that it was sullicient to benzoylize the alkamins hereinbefore mentioned (i. 6., such which contain a tertiary alcohol group) in order to obtain analgetic (locally anesthetic) media, which act just as strongly, but less toxic (poisonous) than cocaine, and are, furthermore, easily soluble in the form of chlorhydrogen combinations (hydrochlorates) and are likewise easily sterilizable.

When it was attempted to exert locallyanesthetizing effects, reference was always had to cocaine. In this manner, for example, the eucaines were found, which, apart from tropacocaine, were hitherto alone able to stand comparison with cocaine. The essential difierence which exists between the eucaines, especially eucaine beta and the compounds obtainable from the alkamins to be here represented, hardly needs special explanation here. caine are derivatives of pyridin, and it is well The eucaines and tropaco-' known what great influence the pyridin Hernel exerts on the degree of poisonousness of these bodies. Furthermore, these bodies are derivatives of secondary alcohols; but it could not be foreseen that such simple bodies-as, for instance, methylor dimethylaminobenzoyl methylpropanol, (dimethylamino dimethylhenzoyl carbinol,) which are derived from the tertiary butylalcohol CH3 CI I3 JOH would possess qualities which had hitherto been ascribed to a number of complicated representatives of organic chemistry and which had been met in this highdegree only in the derivatives of pyridin. Thealkamins of the structure 1 /R3 (JH2-N R1*%OH R2 (R and R, =alkyl or ar'yl or aralkyl R, and R alkyl or hydrogen) therefore as valuable substances possess technical importance. Furthermore, these bodies are not only all new, but they belong to a new type and form a sharply-defined class by themselves in organic chemistry. For their production dimethylamin or another desired secondary or primary amin is allowed to act on the corresponding halogenhydrins, and that according to the general method for producing alkamins. (Ladenburg B. 14, p. 1875. 2407, Wurtz, Liebigs A'rmclen, 121, p. 228, &c.)

The halogenhydrins can easily be obtained by Grignards method, which was employed by Tifieneau for chloracetone, as well as the ester of chloracetic acid. ((omptes-Rendus de ZAcademte des Sciences, 1902, p. 775.)

Example Production of methylchlormethylisoamyl-carbinol: An ether solution of an equivalent of isoamylmagnesium bromid free from water is made, and to the same there is added drop by drop with simultanenamely, chlortrimethylcarbinol, methylchlormethylethylcarbinol, and methylchlor-meth yl-phenylcarbinol; but the others, the production of which corresponds to that of methylare 1. Methylchlormethylpropylcarbinol (llHzCl CH3CH2.UH2-O OH Boils at under twenty-eight millime ters pressure.

2. Chlorinethyldiethylcarbinol:

CZHB

Boils at 88 under thirty-five millimeters pressure.

3. Methylchlormethylisobutylcarbinol:

Boils at under twenty-five millimeters pressure.

4. Methylchlormethylisoamylcarbino1:

CHzCl on l o1r ciaoH.-o -0H CH3 I Boils at 96 to 98 under twenty-three mil- Iimeters pressure.

5. Met ylchlormethylbenzylcarbinol:

I CHzCl CtHa. CH2(lOH chlormethylisoamylcarbinol, are new. These- Boils at 155 under twenty-five millimeters pressure.

Some of these chlorhydrins turn black very rapidly in the air, others, on the other hand, but very slowly. In order to produce the corresponding alkamins from the halogenhydrins, it is sufficient to heat the latter with monomethylamin, dimethylamin, or any other primary or secondary base in the presence of benzol or alcohol as a solvent.

Example I: Production of dimethylaminomethyldiethylcarbinol on. cH.-N

| ons can-c-on A molecule of chlorhydrin (chlormethyldiethylcarbinol) boiling at 88 under thirtyfive millimeters pressure is heated in the pressure-boiler for a day at about 130?,

with more than two molecules of dimethylamin dissolved in a suitable solvent.

The product of reaction is distilled off at normal pressure in order to remove the largest part of the solvent, as well as the dimethylamin, which has not entered into reaction. The remaining mass is then subjected with rarefication of air to a fractionated distillation, or according to a method which takes more time, but yields a purer roduct, the mass of reaction is treated wit diluted muriatic acid in order to bring the base in solution. The acid reacting solution is repeatedly shaken with benzol (which takes 11 the neutral substance, as well-as the chlor ydrin which has not entered into reaction) and almost completel distilled. The remaining mass is with carbonate of soda and thereupon extracted with benzol or ether. The solution, dried With heated carbonate of potassium, is evaporated, and finally the remaining mass is subjected with rarefaction of air or ordinary atmospheric pressure to a fractional distillation. The yield is eighty per cent. on the average. Thebase obtained boils at 76 to 79 under twenty-three millimeters pressure. It consists of an almost wholly colorless liquid of slight odor which is very soluble in water and yields salts difficult to crystallize. A characteristic is the chlorhydro en compound (hydrochlorate) of the benzoy-ized. derivative, which crystallizes out of alcohol in beautiful and shining tablets, which melt at about 189. All other alkamins cited in the present application have been obtained in similar manner. If you proceed from the iodin hydrin, a heating is not necessary.

IT. Di1nethylaln'inotrimethylcarbinol:

cu. The chlorhydrin, (chlortrimethylcarbinol pose in the air and melt at 202.

III. Dimethylaminodimethylethylcarbinol:

CH3 Obtained by the" action of dimethylamin on the corresponding chlorhydrin (methylchlor!nethylethylcarbinol,) (Tifl'eneau, loco citato) which boils at 150. This base consists of a liquid which boils at 57 under twenty-three millimeters pressure. This liquid is almost entirely colorless, very easily soluble in all solvents, and more easily soluble in cold than in warm water. The majority of its salts are difiicult -to crystallize. The platinum salt is very soluble in water. The gold salt crystallizes in little leaves, easily decomposable, and which are but slightly soluble in water. The chlorhydrogen compound of the benzoylized derivative crystallizes in .very small crystals out of saturated solutions in absolute ethyl alcohol. It melts at 17 5;

IV. Dimethylaminodimethylpropylcarbinol:

cHacHtcn cPoH The correspmiding chlorhydrin (methylchlormethylpropylcarbinol) boils at under twenty-eight millimeters pressure. The base is very soluble in water, boils at 78 under thirty-iive millimeters pressure. Furthermore, its salts are uncrystallizable. The chlorhydrate of the benzoylized derivative melts at 146 and crystallizes in fine needles very easily soluble in water and alcohol, which needles are )recipitated by other out of the alcoholic solution. This body is hygroscopic.

Y. Dimethylaminodimethylisobutylcarbino The chlorhydrin (methylchlormethylisobutylcarbinol) boils at under twentyfive millimeters pressure. The base, on the other hand, at+ 82 under thirty-four millimeters pressure. The chlorhydrate of /the benzoylized derivative melts at 134. This body is easily soluble in alcohol and water, but insoluble, on the other hand, in ether.

VI. Dimethylaminodimethylisoamylcarbinol: The chlorhydrin (methylchlormethylisoamylcarbinol) boils at 96 to 98 under twenty-three millimeters pressure; the base, on the other hand, at 98 to 99 under twentyfour millimeters pressure. The body possesses a strong odor and is but very slightly soluble in water. Furthermore, it colors very soon under the influence of the air. The chlorhydrate of its benzoylized derivative crystallizes out hol in beautiful silk-like needles, which are very easily soluble in alcohol, soluble with much difficulty in ether, and melt at 138.

VII. Methylaminodimethylphenylcarbinol is obtained by doubly decomposing methylamin with methylchloror methyliodinmethylphenylcarbinol The correspondinghalogenhydrins (methylhalogenmethylphenylcarbinols) have been described by Tiiieneau. The base, which boils at 135 to 138 under thirty-one millimeters pressure, is very slightly soluble in cold water, and almost entirely insoluble in boiling water. The chlorhydrate precipitated out of acetone has the form of fine little leaves and melts at 153. The dibenzoyl of a mixture of ether alcoderivate melts at 122 and crystallizes out of petroleum ether in beautiful octahedral, shining, and hard crystals.

I If the methylamin in the preceding exam ple is replaced by dimethylamin, there is obtained VIII. Dimethylaminodimethylphenylcartwo millimeters pressure. The chlorhydrate crystallizes out of acetone in small leaves which melt at 159 to 160. The chlorhydrate of the benzoyl derivative is very little soluble in alcohol and in water, but very easily soluble, on the other hand, in warm methyl alcohol and crystallizes out of the same after coolingin beautiful shining little mitting benzyl magnesium chlorid to act upon tablets, which-melt at 205 to 206.

IX. Diethylaminodimethylphenylcarbinol:

is obtained by allowing diethylamin, in place of dimethylamin, (see Example 8,) to act upon This body represents a thick liquid which boils at 147 to 149 under twenty-four millimeters pressure. The salts are crystallizable with great difficulty. The chlorhydrate of the benzoylized derivative of this product is syrupy.

X. D1methylammodimethylbenzylcarbinol:

CH3 OH2N on. o.H5 cH. 1-oH The chlorhydrin, which is obtained by perchloracetone, boils at 155 under twenty-five millimeters pressure. The base boils at 144 under twenty'four millimeters pressure. The chlorhydrate of the benzoyl derivative crystallizes out of'absolute alcohol in very fine needles and out of methyl alcohol in beautiful, transparent, and hard prisms, which melt at 195.

The following may be cited as examples for the roduction of alkamins from the corresponding bromidor iodinhydrins:

the corresponding halogenh'ydrin.

.the corresponding ethylene oxid (which results from the action of caustic potash on the chlordimethylisomylcarbinol described in the application) with. ethylmagnesium bromid. This reaction is identical with that which is yielded by the bromidhydrin of glycol when you proceed from ethylenoxid, (Blaise, Oomptes-Rendus de F110. (1. Sci. 134, p. 551.) This bromid hydrin boils at 130 under thirty seven millimeters pressure. Ten gr. of the bromidhydrin are heated for one day at 100 with double the theoretical quantity of dimethylamin in a thirty-pencent. benzol solution in a tube sealed by melting or otherwise closed. The base is isolated exactly as it was done with the chlorhydrin. In this manner there are obtained 4.8 g. of the dimethylaminodimethylisoamylcarbinol already described in Example VI and the chlorhydrate of which melts at 142 and crystallizes out of an alcohol ether mixture in fine hygroscopic little leaves. XII. Iodindimethylphenylcarbinol This iodinhydrin was produced by Tifien- I00 can (0. R. de Z'Ac. d. S0. 134, p. 847) by the action of subiodic acid (Lipmann, 0. R. de P140. d. 80. 63, p. 68) upon methethenylphen. Seventy g. of the iodinhydrin are treated at ordinary temperature with twice the 105 theoretical quantity of dimethylamin in. a thirty-per-cent. benzoyl solution. After three days the dimethylaminiodinhydrate which has been formed is thrown out and-the base is isolated exactly like the one which is 1 [0 derived from the corresponding chlorhydrin, (Example VIII.) In this manner there are obtained about twenty-two g. dimethylaminodimethylphenylcarbinol, the properties of which have already been recounted in the de- 1 I 5 scription.

I claim as my invention- 1. The process for producing aminoalcohols of the formula substantially as herein described:

/CH2-N 3 said process consisting in reacting "on halogenhydrins of the structure CH2Cl(1.Br.)

with aliphatic-21mins.

2-. The process for producing aminoalcohols of the formula substantially as herein 10 described said process consisting ill reacting on halo- I5 genhydrins of the structure CH2Cl(1.Br.) ro

- 20 With primary aliphatic-amins.

In testimony whereof I have signed my name to this specification in the presence of two subscribing Witnesses.

ERNEST FOURNEAU.

Witnesses:

ANTONIN MQNTEILHET, HANSON C. 'COXEQ 

